Anti-HIV pharmaceutical formulations

ABSTRACT

The preferred oligomers of the present invention are polyureas, polycarbonates, polyesters or polyamides having a number average molecular weight of &lt;10,000. These oligomers are water-soluble, have a rigid backbone, have recurring units coupled by carbonyl linking moieties which have anionic groups, display predominantly linear geomentry such that regular spacing between anionic groups exists in an aqueous medium, and are pharmaceutically-acceptable. The oligomers are useful for the treatment and/or diagnosis of AIDS and ARC.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a division of U.S. Ser. No. 08/132,551, filedOct. 6, 1993, now U.S. Pat. No. 5,608,108, which is a division of U.S.Ser. No. 07/710,370, filed Jun. 10, 1991, now U.S. Pat. No. 5,276,182,which is a continuation-in-part of U.S. Ser. No. 07/549,782 filed Jul.9, 1990, now abandoned, herein incorporated by reference.

This invention concerns oligomers, their uses and formulations, as wellas processes for their preparation. The present oligomers are anioniccompounds that have particularly valuable anti-human immunodeficiencyvirus activity and these oligomers are thus useful in the treatment ofacquired immune deficiency syndrome (AIDS).

BACKGROUND OF THE INVENTION

A great deal of research is currently underway to develop treatments andcures for viral infections in humans and in animals. Notably theincidence of AIDS and AIDS related complex (ARC) in humans is increasingat an alarming rate. The five year survival rate for those with AIDS isdispiriting and AIDS patients, whose immune systems have been seriouslyimpaired by the infection, suffer from numerous opportunistic infectionsincluding Kaposi's sarcoma and Pneumocystis carninii pneumonia. No curefor AIDS is known and current treatments are largely without adequateproof of efficacy and have numerous untoward side effects. Fear of thedisease has resulted in social ostracism of and discrimination againstthose having or suspected of having the disease.

Retroviruses are a class of ribonucleic acid (RNA) viruses thatreplicate by using reverse transcriptase to form a strand ofcomplementary DNA (cDNA) from which a double stranded, proviral DNA isproduced. This provital DNA is then randomly incorporated into thechromosomal DNA of the host cell making possible viral replication bylater translation of viral message from the integrated viral genome.

Many of the known retroviruses are oncogenic or tumor causing. Indeed,the first two human retroviruses discovered, denoted human T-cellleukemia viruses I and II or HTLV-I and II, were found to cause rareleukemias in humans after infection of T-lymphocytes. The third suchhuman virus to be discovered, HTLV-III, now referred to as HIV, wasfound to cause cell death after infection of T-lymphocytes and has beenidentified as the causative agent of AIDS and ARC.

The envelope protein of HIV is a 160 kDa glycoprotein. The protein iscleaved by a protease to give a 120 kDa external protein, gp120, and atransmembrane glycoprotein, gp41. The gp120 protein contains the aminoacid sequence that recognizes the CD4 antigen on human T-helper (T4)cells.

One approach being explored is to prevent the binding of HIV to itstarget, the T4 cells in humans. These T4 cells have a specific region, aCD4 antigen, which interacts with gp120. If this interaction can bedisrupted, the host cell infection can be inhibited.

Interference with the formation of the viral envelope glyoprotein couldprevent the initial virus-host cell interaction or subsequent fusion orcould prevent viral duplication by preventing the construction of theproper glycoprotein required for the completion of the viral membrane.It has been reported See H. A. Blough et al., Biochem. Biophys. Res.Comm. 141(1), 33-38 (1986)! that the nonspecific glycosylationinhibitors 2-deoxy-D-glucose and β-hydroxy-norvaline inhibit expressionof HIV glycoproteins and block the formation of syncytia. Viralmultiplication of HIV-infected cells treated with these agents isstopped, presumably because of the unavailability of glycoproteinrequired for the viral membrane formation. In another report W. McDowellet al., Biochemistry 24(27), 8145-52 (1985)!, the glycosylationinhibitor 2-deoxy-2-fluoro-D-mannose was found to inhibit antiviralactivity against influenza infected cells by preventing theglycosylation of viral membrane protein. This report also studied theantiviral activity of 2-deoxyglucose and 2-deoxy-2-fluoroglucose andfound that each inhibited viral protein glycosylation by a differentmechanism. However, other known glycosylation inhibitors have been shownto have no antiviral activity. Thus the antiviral activity againstviruses in general, and the viral activity specifically, ofglycosylation inhibitors is quite unpredictable.

It has been disclosed in U.S. application Ser. No. 295,856, filed Jan.11, 1989, U.S. Pat. No. 5,272,261 that a purified form of heparin, asulfated polysaccharide, binds through interactions to a viral proteinwhich is responsible for cell recognition and provides limitedinhibition of host cell infection. However, heparin causes some sideeffects, notably hemorrhage and increased clot formation time as well asthrombocytopenia. Use of heparin is contraindicated in patients who areactively bleeding, or have hemophilia, purpura, thrombocytopenia,intracranial hemorrhage, bacterial endocarditis, active tuberculosis,increased capillary permeability, ulcerative lesions of thegastrointestinal tract, severe hypertension, threatened abortion orvisceral carcinoma. The contraindication for use by hemophiliacs isparticularly of concern because many such individuals are now HIVpositive.

It has long been recognized that certain synthetic, water-solublepolymers exhibit a broad spectrum of biological activity R. M.Ottenbrite in "Biological Activities of Polymers", Amer. Chem. Soc.Symp. Ser. No. 182, pp. 205-220, eds. C. E. Carraher and C. G. Gebelein(1982)!. A copolymer of divinyl ether and maleic anhydride has beenshown to be active against a number of viruses and its use in cancerchemotherapy has been studied for years Breslow, D. S. Pure and AppliedChem. 46, 103 (1976)!. Polyacrylic, polymethacrylic and a variety ofother aliphatic backbone water soluble polymers also have been shown tohave a broad spectrum of biological activities W. Regelson et al.,Nature 186, 778 (1960)!. Unfortunately, the extreme toxicity of thesepolymers has prevented their clinical use. Also, these polymers have ahigh molecular weight and are unable to pass through the renalmembranes.

Attempts have been made to circumvent the toxicity and excretionproblems by synthesis of low molecular weight (1,000 to 10,000)aliphatic polymers R. M. Ottenbrite in "Biological Activities ofPolymers", Amer. Chem. Soc. Symp. Ser. No. 182, pp. 205-220, eds. C. E.Carraher and C. G. Gebelein (1982)!. It has been found that suchpolymers are less toxic but have much reduced antiviral activity. Theselow molecular weight aliphatic polymers may be classed as "random coil"polymers. Such polymers have an unpredictable configuration because ofthe flexibility of the backbone linking groups. The configuration ofrandom coil polymers in solution may be generally described as globular.Although the mechanism of action of such water-soluble polymers isunknown, one postulate is that the polymer binds to the viral membrane,e.g. encephelomyocarditis, through an ionic attraction, thus renderingthe virus unable to infect host cells.

An additional synthetic polymer approach is to place ionic groups on thebackbone of a polymer which exhibits a more defined geometry. There arenumerous examples of non-ionic, synthetic polymers which exhibit a morelinear geometry in non-aqueous solution than do the aliphatic polymersdescribed above J. Macromolecular Sci-Reviews in Macromol. Chem. Phys.C26(4), 551 (1986)!. The factors involved which cause this non-randomcoil structure are complex and poorly understood. In general, suchpolymers have either a very limited number of rotatable bonds which arenot parallel to the polymer axis, or there is hydrogen bonding ordipolar interactions which favor linear structures. These polymers arereferred to as having a "rigid backbone". A polyamide derived fromterephthalic acid and p-diaminobenzene (known commercially as Kevlar™supplied by DuPont) is a well-known example of such polymers.

Synthetic, water-soluble, rigid polymers are much less common, but a fewhigh molecular weight examples are known (e.g. see U.S. Pat. Nos.4,824,916 and 4,895,660). The non-random coil structure of this class ofpolymer results in high solution viscosities for a given molecularweight and concentration.

Clearly, it would be desirable to find a treatment and cure for AIDS andARC which would display minimal or no side effects and constitute aclear improvement over the polymers previously employed as apharmaceutical.

SUMMARY OF THE INVENTION

It has now been discovered that anionic oligomers inhibit viralreplication without the side effects shown by heparin and knownpolymers. The oligomers have an ordered anion spacing, have a rigidbackbone and are water-soluble.

The novel oligomers of the present invention are anionic, carbonylcontaining compounds. Examples of such oligomers are polyureas,polycarbonates, polyesters or polyamides having a number averagemolecular weight, M_(n), of <10,000 which are water-soluble, have arigid backbone, and have an ordered anion spacing. The oligomers includetheir salts, which are pharmaceutically-acceptable when used aspharmaceutical agents.

Other uses for these anionic oligomers are as effective thickeningagents in aqueous solutions, or as mild ionic detergents. In general,water soluble polymers, including those oligomers of the presentinvention, have a wide spectrum of uses as thickeners, dispersants, andflocculants. The present oligomers may be used in applications for oilfields, mining, paper manufacturing, textile manufacturing, cosmeticingredients and manufacturing, and food processing. Additionally thepresent low molecular weight polymers, i.e. oligomers, may be used asstarting materials for the preparation of high molecular weight polymersand copolymers.

Thus, this invention concerns a water-soluble, rigid backbone oligomerhaving a molecular weight less than (<) 10,000 comprising recurringunits coupled by carbonyl linking moieties, said oligomer having anionicgroups and predominantly linear geometry such that regular spacingbetween anionic groups exists in an aqueous medium. Preferably eachrecurring unit has at least two anionic groups.

Any oligomer which meets the above criteria can be used in thisinvention. Particularly preferred oligomers are those which arepolyureas, polycarbonates, polyesters or polyamides. These oligomerspreferably assume a linear geometry.

DETAILED DESCRIPTION OF THE INVENTION

The novel oligomers of the present invention are illustrated bypolyureas, polycarbonates, polyesters or polyamides having a numberaverage molecular weight M_(n) of <10,000 which are water-soluble, havea rigid backbone, have an ordered anion spacing and a predominantlylinear geometry in an aqueous medium. The oligomers are preferablylinear in their backbone and also may be in their salt form,particularly preferred salts are those that arepharmaceutically-acceptable.

The preferred oligomers of this invention are represented by any one ofthe following formulae:

A) a polyurea of the formula: ##STR1## wherein:

R represents a hydrogen atom, a C₁ -C₄ alkyl group, a phenyl group, or aphenyl group substituted with from 1 to 2 R¹ moieties and up to 3substituents independently selected from a chloro or bromo atom or C₁-C₄ alkyl group;

R¹ represents --SO₃ R², --CO₂ R², --PO₃ (R²)₂, or --OPO₃ R₂ ;

R² represents a hydrogen atom or a pharmaceutically-acceptable cation;

m is an integer 0 or 1, with the proviso that when m is 0, R is ahydrogen atom;

X represents ##STR2##

Y represents --CO₂ --, --C.tbd.C--, --N═N--, ##STR3##

n is an integer from 3 to 50; and

R³ represents --R or --X--NH₂, where R and X are defined as before;

B) a polycarbonate of the formula: ##STR4## wherein;

X and n are defined as in Formula I above;

X¹ represents a HO--X-- group, where X is defined as for Formula Iabove, or a C₁ -C₄ alkyl group, a phenyl group, or a phenyl groupsubstituted with from 1 to 2 R¹ moieties and up to 3 substituentsindependently selected from a chloro or bromo atom or C₉ -C₄ alkylgroup; and

X² represents a hydrogen atom, or --CO₂ X¹, where X¹ is defined asabove;

C) a polyester of the formula ##STR5## wherein:

X and n are defined as in Formula I above;

R⁴ represents --R², as defined in Formula I, or --X¹, as defined inFormula II above;

R⁵ represents ##STR6## where R⁴ is defined as in Formula III above, or--R², where R² is defined as in Formula I above;

X³ represents ##STR7## wherein R¹ and Y are defined as in Formula Iabove; or

D) a polyamide of the formula: ##STR8## wherein:

X and n are defined as in Formula I above;

X³ is defined as in Formula III above;

R⁶ represents H₂ N--X--NH--, R² O--, RNH-- or R--C(O)--NH--X--NH--,where R, R² and X are defined as in Formula I;

R⁷ represents a hydrogen atom, ##STR9## where R and R² are defined as inFormula I above; and

X³ is defined as in Formula III above.

The term "pharmaceutically-acceptable cation" means a cation acceptablefor pharmaceutical use. Those cations that are not substantially toxicat the dosage administered to achieve the desired effect and do notindependently possess significant pharmacological activity are includedwithin the term "pharmaceutically-acceptable cation". illustratively,these salts include those of alkali metals, such as sodium andpotassium; alkaline earth metals, such as calcium and magnesium;ammonium; light metals of Group IIIA including aluminum; and organicprimary, secondary and tertiary amines, such as trialkylamines,including triethylamine, procaine, dibenzylamine,N,N'-dibenzylethylenediamine, dihydroabietylamine, N-(C₁-C₄)alkylpiperidine, and any other suitable amine. Sodium and potassiumsalts are preferred. The term "pharmaceutically-acceptable" meanssuitable for administration to warmblooded animals, especially humanbeings, and includes being nontoxic, e.g. suitable for pharmaceuticaluse and is not poisonous to the warm-blooded animal. Thepharmaceutically-acceptable cations of the oligomers of the presentinvention are prepared by conventional ion exchange processes or bytreating the R¹ acid with an appropriate base.

When uses other than for pharmaceuticals are the object for the presentoligomers, then salts that would otherwise not be as acceptable forpharmaceutical uses may be employed. Examples of such additional saltsinclude barium, zinc and titanium.

The oligomers of the present invention are low molecular weight, rigidbackbone, water-soluble polymers. Additionally, the oligomers haveordered anion spacing. By "ordered onion spacing" or "regular spacingbetween anionic groups" is meant that the anionic groups (R¹) arepresent in the backbone of the polymer at intervals determined by thestarting material reagent used and the occurrence of the anionic groupsis controlled in a predictable manner. While not wishing to be bound byany theory, the anionic groups of the oligomers are believed to be theportion that binds to the HIV and/or cell membrane and therebyinterrupts the ability of the virus to replicate.

The terms "predominantly linear geometry" in an aqueous medium refers tothe solution configuration of the oligomer. A method well known in theart for characterization of the solution configuration of polymermolecules is based on the following formula, referred to as theMark-Houwink equation "Introduction to Physical Polymer Science", ed. L.H. Sperling, pub. John Wiley & SONS (1985), pp. 81-83!,

     η!=KM.sup.α

wherein η is intrinsic viscosity; M is weight average molecular weight;K is a constant related to chain bond dimension; and α is a constantdetermined by polymer configuration. The intrinsic viscosity (η) for arandom coil polymer is 0.5<α<0.9; and for a linear polymer is0.9<=α<1.8. This formula relates the solution viscosity "η" to themolecular weight "M". For this invention linear polymers are defined ashaving "α" values greater than or equal to 0.9. For a rigid rod polymerthe theoretical upper limit is 1.8. For a given molecular weight, ahigher solution viscosity will be obtained from polymers with a linearconfiguration relative to those polymers which exist as a random coil.An additional consideration is that the "α" value is a function of thesolvent used. The "α" for a given water soluble polymer may be differentat different salt concentrations. For this invention, the saltconcentration is set at the levels present in serum (approximately 80g/L NaCl, 4 g/L KCl).

As used herein, the term "oligomer" encompasses all the possible valuesfor n, e.g., 3 through 50. The oligomers are preferably linear with nequal to an integer from 3 to 50, preferably from 3 to 20, morepreferably from 3 to 15. Of course, the n value is directly related tothe molecular weight of the resulting oligomer. It is essential thatthese oligomers are of sufficiently low molecular weight in order topass through the renal excretory membrane, but able to inhibit the HIVvirus. The average molecular weight is governed by the stoichiometry ofthe reagents. The number average molecular weight (M_(n)) is <10,000,preferably from about 500 to about 10,000, and most preferably fromabout 1,000 to about 6,000.

For the purpose of the present invention, the oligomers described hereinand physiologically-acceptable salts thereof are considered equivalent.Physiologically-acceptable salts refer to the salts of those bases whichwill form a salt with at least one acid group of the R¹ group and whichwill not cause significant adverse physiological effects whenadministered as described herein. Suitable bases include, for example,the alkali metal and alkaline earth metal hydroxides, carbonates, andbicarbonates such as sodium hydroxide, potassium hydroxide, calciumhydroxide, potassium carbonate, sodium bicarbonate, magnesium carbonateand the like, ammonia, primary, secondary and tertiary amines and thelike. Particularly preferred bases are the alkali metal hydroxides,carbonates, and bicarbonates. Physiologically-acceptable salts may beprepared by conventional ion exchange processes or by treating the R¹acid with an appropriate base. Examples of additional salts have beendescribed herein.

The formulations of the present invention are in the solid or liquidform. These formulations may be in kit form such that the two componentsare mixed at the appropriate time prior to use. Whether premixed or as akit, the formulations usually require a pharmaceutically-acceptablecarrier or adjuvant.

The oligomers of the present invention are soluble in water and in saltsolutions, especially at physiological pH and in saline solutions. Thusthe present oligomers are readily formulated into a suitable aqueouspharmaceutical dosage form. Also, after the present oligomer formulationis administered, the oligomer remains soluble in vivo.

Preferred terms for the previously described Formulae I to IV are asfollows:

R and R³ are a 4-methylphenyl group;

m is 1;

n is 3 to 15;

R⁴ and R⁵ are hydrogen;

R⁶ is phenyl;

R⁷ is benzoyl;

X¹ is a 4-methylphenyl group;

X² is --CO₂ -(4-methylphenyl) group;

X³ represents ##STR10##

X represents ##STR11## while especially preferred is ##STR12##

Anti-HIV anionic oligomers can be used to prevent syncytium formation incells infected with HIV-I virus or other related viruses having gp120surface protein. Anti-HIV anionic oligomers can be used to treat AIDSand ARC and other diseases caused by the retrovirus HIV-I or otherrelated viruses having gp120 surface protein. The anionic oligomers ofthis invention can be used as a pure compound, or as mixtures, such asthose of n values of a particular Formula I to IV, or mixtures of morethan one Formula, e.g., Formula I with Formula II compounds, or asmixtures with other known agents for the present anti-viral utilities.However, for all oligomers prepared, n represents the number averagerepeat length of the distribution through all formulae.

The amount of anti-HIV anionic oligomers which is needed to preventsyncytium formation in HIV infected cells can be any effective amount.Experimentally, it has been determined that anti-HIV anionic oligomers,when employed at a concentration of 10 μg/mL of aqueous formulation,resulted in complete inhibition of syncytium formation as well asreduced the presence of p24 antigen, an indicator of vital replication,to below 300 pg/ml. The amount of anti-HIV anionic oligomers to beadministered in order to treat AIDS or ARC or other disease caused byHIV infection can vary widely according to the particular dosage unitemployed, the period of treatment, the age and sex of the patienttreated, the nature and extent of the disorder treated, and otherfactors well-known to those practicing the medical arts. Moreoveranti-HIV anionic oligomers can be used in conjunction with other agentsknown to be useful in the treatment of retroviral diseases and agentsknown to be useful to treat the symptoms of and complications associatedwith diseases and conditions caused by retroviruses.

The anti-HIV effective amount of anti-HIV anionic oligomers to beadministered according to the present invention will generally rangefrom about 0.1 mg/kg to 500 mg/kg of body weight of the patient and canbe administered one or more times per day. Anti-HIV anionic oligomerscan be administered with a pharmaceutical carrier using conventionaldosage unit forms either orally or parenterally.

For oral administration, anti-HIV anionic oligomers can be formulatedinto solid or liquid preparations such as capsules, pills, tablets,troches, lozenges, melts, powders, solutions, suspensions, or emulsions.The solid unit dosage forms can be a capsule which can be of theordinary hard- or soft-shelled gelatin type containing, for example,surfactants, lubricants, and inert fillers such as lactose, sucrose,sorbitol, calcium phosphate, and cornstarch. In another embodiment theanionic oligomers of this invention can be tableted with conventionaltablet bases such as lactose, sucrose, and cornstarch in combinationwith binders such as acacia, cornstarch, or gelatin, disintegratingagents intended to assist the break-up and dissolution of the tabletfollowing administration such as potato starch, alginic acid, cornstarch, and guar gum, lubricants intended to improve the flow of tabletgranulations and to prevent the adhesion of tablet material to thesurfaces of the tablet dies and punches, for example, talc, stearicacid, or magnesium, calcium, or zinc stearate, dyes, coloring agents,and flavoring agents intended to enhance the aesthetic qualities of thetablets and make them more acceptable to the patient. Suitableexcipients for use in oral liquid dosage forms include diluents such aswater and alcohols, for example, ethanol, benzyl alcohol, and thepolyethylene giycols, either with or without the addition of apharmaceutically-acceptable surfactant, suspending agent, or emulsifyingagent.

The anti-HIV anionic oligomers of this invention may also beadministered parenterally, that is, sub-cutaneously, intravenously,intramuscularly, or inter-peritoneally, as injectable dosages of theanionic oligomers in a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, etherssuch as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acidester or glyceride, or an acetylated fatty acid glyceride with orwithout the addition of a pharmaceutically acceptable surfactant such asa soap or a detergent, suspending agent such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fattyacids include oleic acid, stearic acid, and isostearic acid. Suitablefatty acid esters are, for example, ethyl oleate and isopropylmyristate. Suitable soaps include fatty alkali metal, ammonium, andtriethanolamine salts and suitable detergents include cationicdetergents, for example, dimethyl dialkyl ammonium halides, alkylpyridinium halides, and alkylamines acetates; anionic detergents, forexample, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, andmonoglyceride sulfates, and sulfosuccinates; nonionic detergents, forexample, fatty amine oxides, fatty acid alkanolamides, andpolyoxyethylenepoly-propylene copolymers; and amphoteric detergents, forexample, alkyl-beta-aminopropionates, and 2-alkyl-imidazolinequarternary ammonium salts, as well as mixtures. The parenteralcompositions of this invention will typically contain from about 0.5 toabout 25% by weight of anti-HIV anionic oligomer in solution.Preservatives and buffers may also be used advantageously. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulations ranges from about 5 to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB. Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate.

The oligomers of this invention can also be used prophylactically, thatis, to prevent transmission of virus from an infected individual to anuninfected target. Virus is spread proportionally via exchange of bloodbut may be transmitted via exchange of other bodily fluids as well. Thusthe oligomers of this invention can be formulated with standarddetergent products for use in cleaning, particularly in research andclinical laboratories and in hospitals where blood products of infectedindividuals are handled. Formulations containing the oligomers of thepresent invention can be used to clean medical/surgical equipment andutensils as well as the hands of and other skin areas of health careworkers. The oligomers of this invention can also be applied, as aliquid or powder composition, to the surface of sexual prophylaxis suchas condoms by either the user or manufacturer of the prophylaxis priorto sale. The oligomers of this invention can be formulated into a douchecomposition for use by females for use prior to subsequent sexualcontact with an infected individual. The oligomers of this invention canalso be formulated in lubricants and spermatacidal jellies and lotions.Finally, the oligomers of this invention can also be formulated ascompositions to be added to hot tubs, whirlpool baths and swimming poolsto inactivate potential virus activity.

Definitions

The terms used in the present application are defined as follows:

n represents the number average repeat length of the distributionthrough all formulae.

RPMI means a cell culture media.

TC ID50 means tissue culture infectious unit, i.e. the amount of culturefluid effective to infect 50% of the cells.

MTT means 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

MT4 means a cell line.

P24 test-Abbott means an assay of the viral core antigen using the assaykit currently sold by Abbott.

Coulter™ HIV assay means a radioimmuno assay for P24 viral antigendetermination.

rs CD₄ means recombinent soluble CD₄ comprised of the fourextracytoplasmic immunoglobulin like variable (V) domains V₁ -V₄.

T means 4-methylaniline or toluidine, except when using the term "T4cells" or "T-helper cells".

P means phosgene.

C means p-cresol.

MBC means 4-methylbenzoyl chloride.

TPC means 1,4-benzenedicarbonyl chloride or terephthaloyl chloride.

TPCS means sodium 2,5-bis(chlorocarbonyl)-benzenesulfonate, having theformula ##STR13##

HBDS means dipotassium 2,5-dihydroxy-1,4-benzenedisulfonate, having theformula ##STR14##

HBPDS means dipotassium 4,4'-dihydroxy(1,1'-biphenyl)-2,2'-disuifonate,having the formula ##STR15##

PDS means 2,5-diamino-1,4-benzenedisulfonic acid, having the formula##STR16##

BPDS means 4,4'-diamino-(1,1'-biphenyl)-2,2'disulfonic acid, having theformula ##STR17##

StDS means means trans-2,2'-(1,2-ethenediyl)bis(5-aminobenzenesulfonicacid), having the formula ##STR18##

BPDS/P/T means poly{imino2,2'-disulfo(1,1'-biphenyl)-4,4'-diyl!imino-carbonyl}, alpha-{(4-methylphenyl)amino!carbonyl}-omega- (4-methylphenyl)amino!- and isrepresented by Formula I above when R is 4-methylphenyl, R² is hydrogen,X is ##STR19## wherein n is defined as in Formula I.

StDS/P/T means polyimino(3-sulfo-1,4-phenylene)-1,2-ethenediyl-(2-sulfo-1,4-phenylene)iminocarbonyl!,alpha-{ (4-methyl-phenyl)aminocarbonyl}-omega- (4-methylphenyl)amino-and is represented by Formula I above when R is 4-methyl-phenyl, R² ishydrogen, X is ##STR20## where n is defined as in Formula I.

PDS/P/T means poly imino(2,5-disulfo-1,4-phenylene)iminocarbonyl!,alpha-{ (4-methylphenyl)amino!carbonyl}-omega- (4-methyl-phenyl)amino!-and is represented by Formula I above when R is 4-methylphenyl, R² ishydrogen, X is ##STR21## and n is defined as in Formula I.

HBDS/P/C means poly oxy(2,5-disulfo-1,4-phenyiene)oxycarbonyl!, alpha-(4-methylphenoxy)carbonyl!-omega-(4-methylphenoxy)- and is representedby Formula II above when X¹ is 4-methylphenyl, R² is hydrogen, X is##STR22## and n is defined as in Formula I.

HBPDS/P/C means poly{oxy2,2'-disulfo(1,1'-biphenyl)-4,4'-diyl!oxy-carbonyl}, alpha-(4-methylphenoxy)carbonyl!-omega-(4-methylphenoxy)- and is representedby Formula II above when X¹ is 4-methylphenyl, R² is hydrogen, X is##STR23## and n is defined as in Formula I.

HBPDS/TPC means poly{oxy2,2'-disulfo(1,1'-biphenyl)-4,4'-diyl!oxy-carbonyl-1,4-phenylenecarbonyl}-and is represented by Formula III when R⁴ and R⁵ are hydrogen, X³ isp-phenylene, X is ##STR24## where n is defined as in Formula I.

HBDS/TPC means polyoxy(2,5-disulfo-1,4-phenylene)oxycarbonyl-1,4-phenylenecarbonyl!- and isrepresented by Formula III when R⁴ and R⁵ are hydrogen, X³ isp-phenylene, X is ##STR25## where n is defined as in Formula I.

BPDS/TPC/MBC means poly{imino2,2'-disulfo(1,1'-biphenyl)-4,4'-diyl!iminocarbonyl-1,4-phenylenecarbonyl},alpha-{ (4-methylphenyl)amino!carbonyl}-omega- (4-methylphenyl)amino!-and is represented by Formula IV above when R⁶ is R--C(O)--NH--X--NH--,R is 4-methylphenyl, R² is hydrogen, R⁷ is 4-methylbenzoyl, X³ isp-phenylene, X is ##STR26## where n is defined as in Formula i.

The oligomers were prepared by modifying the procedure of Kershner (U.S.Pat. No. 4,895,660, the disclosure of which is hereby incorporated byreference, and described further below) by replacing a portion of one ofthe difunctional monomers with a mono-functional end-capping agent andrunning the reaction in the absence of a surfactant. The number averagemolecular weight (M_(n)) is governed by the stoichiometry of thereactants.

The oligomers of the present invention are prepared by the variousreactions described below.

Polyureas and Polyamides (of Formulae I and III above)

The preferred process for the polyureas and polyamides of Formulae I andIII above is described in the art (Kershner U.S. Pat. No. 4,824,916) andis further explained as follows. The various reactants and conditionsare also described.

Diamines: A wide variety of aliphatic and aromatic diamines areincluded. The hydrocarbylene diradicals of which the diamines arecomposed can include methylene, ethylene, butylene, isopropylidene,phenylene, biphenylene, and other diradicals. The range of possiblesubstituents is similarly broad, and includes hydroxyl, alkenyl, loweralkyl moieties, carboxylate, sulfonate, and halogens. The substituentsare not necessarily anionic at neutral pH in water.

Difunctional Electrophiles: Phosgene (carbonyl dichloride), carbonyldibromide, Cl₃ COCOCl, Cl₃ COCO₂ CCl₃, diacid halides of aliphatic andaromatic dibasic acids such as oxalic, malonic, succinic, glutaric,adipic, sebacic, phthalic, isophthalic, 2,6-naphthalic acids.

Acid Acceptors: Several bases have been employed, such as sodiumcarbonate, sodium hydroxide, and tributylamine.

Miscellaneous additives: Various surfactants may be added. Suitablesurfactants may be non-ionic, such as sorbitan monolaurate, sorbitanmonostearate, ethylene glycol distearate, polyethylene oxy/polypropyleneoxy polymer. Such surfactants can be difficult to remove from theproduct, and therefore the use of surfactants is not preferred.

Solvents: Single solvent process employ polar aprotic solvents such asN,N-dimethylacetamide and N,N-dimethylformamide. Also applicable are acombination of water and a second solvent, such as toluene, carbontetrachloride, benzene, acetone, ethylene dichloride, and the like.Typical ratios of organic to aqueous solvents are about 0.5 to about 2.

In the processes described in the art, the diacid halide is added to astirred solution or suspension of the other starting materials. In someinstances the base is added during the carbonyl dihalide addition. Thetemperature is maintained between 0° and 50° C., preferably 20° to 30°C. A reactant ratio (molar ratio of diamine to diacid halide) from about0.9 to 1.2 may be used, with essentially equimolar amounts preferred.

The reaction is stirred at a rate sufficient to achieve mixing of thereactants. The reaction rate is dependent in part on the interfacialarea between the phases, and therefore vigorous stirring is preferable.A commercial blender may be employed for this purpose.

The process used to prepared the polyureas of the present invention is amodification of the process described above.

Diamines: The diamines of the present invention are primarily aromatic,with the formulas described in previous sections. Such diamines aresubstituted with at least one group which is charged at neutral pH,preferable sulfonate. Monovalent aliphatic substituents are allowable. Asmall set of aliphatic linking groups which tie aromatic radicalstogether may be used such as trans-substituted ethylene and acetylene.Preferred diamines are those in which the carbon-nitrogen bonds areforced to be parallel, such as PDS, BPDS, StDS, and2,5-diaminobenzensulfonic acid.

Difunctional electrophiles: For the preparation of polyureas phosgene(carbonyl dichloride) and carbonyl dibromide, and other urea precursorssuch as carbonyl diimidazole, hexachloroacetone, Cl₃ COCO₂ CCl₃, CCl₃COCl, and Cl₃ OCOCl may be used. For the preparation of polyamides,aromatic diacids such as isophthalic and terephthalic acid (TPC),2,6-napthalenedioic acid. These diacids may have neutral or chargedsubstituents, such as monovalent alkyl radical (methyl, ethyl, butyl)and/or charged groups such as sulfonates, phosphates and the like. Anexample of such a charged difunctional electrophile is sodium2,5-bis(chlorocarbonyl)benzenesulfonate (TPCS).

Acid Acceptors: A variety of inorganic bases may be used, such as alkalimetal or divalent metal hydroxides carbonates, bicarbonates, phosphates.Acid acceptors with buffering capacity are preferred when all of thebase is added prior to the addition of the difunctional electrophile.Organic bases such as trialkyl amines may be used, but are notpreferred.

Monofunctional end capping agent: A variety of such molecular weightlimiting agents may be used. Such agents may be aliphatic or aromaticcompounds which react with the diamines or the difunctionalelectrophiles. Examples of suitable monofunctional agents are aminessuch as aniline, methylaniline, methylamine, ethylamine, butylamine,diethylamine, ammonia N-methylaniline, phenol and cresol. Examples ofmonofunctional amine reactive agents are benzoyl chloride, methylbenzoyl chloride, acetyl chloride, and phenyl chloroformate. Theseend-capping agents may also contain charged substituents, for examplepotassium 2-sulfophenol or potassium 4-sulfoaniline.

Miscellaneous additives: The addition of surfactants is not necessary orpreferred, and can complicate the isolation process.

Solvents: A single solvent, water, is preferred when the difunctionaletectrophile is a liquid at the reaction temperature. An example of sucha difunctional electrophile is phosgene. When solid, water insolublereactants are used, a small amount of a water immiscible cosolvent isdesirable. For example, when terephthaloyl chloride is used a minimumamount of methylene chloride is added to improve the contact between thereactants. Example of such water immiscible cosolvents are chloroform,carbon tetrachloride, toluene, and methylene chloride. Typical ratios oforganic to aqueous solvents are 0 to 1, with 0 to 0.1 preferred.

The process is conducted at temperatures which allow the reaction toproceed, typically from about 0° to 100° C. Preferable temperatures are0° to 25° C. When low boiling starting materials are used, for examplephosgene (bp 6° C.), it is advantageous to operate at temperatures at orbelow the boiling point. The pressure is not important and typicallyambient pressure is employed. The pH of the reaction must be carefullymaintained for optimum process. At low pH (<6) the reaction is veryslow, while at high pH (>10) the difunctional electrophile is unstableto attack by hydroxide or other base. Degradation of the polyurea canalso occur at high pH. The pH is preferably maintained between 7 and 9.

When no end capping agent is used, molecular weight control can beachieved by careful adjustment of the stoichiometry of the reactants.Either the diamine or the difunctional electrophile may be used inexcess, for example from 1 to 100% molar excess. This stoichiometry mustaccount for any of the difunctional electrophile which is destroyed byhydrolysis prior to reaction with the diamine. For example, whenphosgene is used at high pH, a large excess is required to compensatefor the fast reaction with hydroxide which destroys it. Because theextent of this side reaction is difficult to control, a monofunctionalend capping agent is preferably used to control the molecular weight.Although the techniques mentioned can be used to control the numberaverage molecular weight, the products are mixtures of polymers withseveral molecular weights characterized by a distribution.

The order of addition of the reactants is not critical. However, thepreferred order is to add the difunctional electrophile first. When acidacceptors which are not buffers are used, such as hydroxide, it is mostpreferable to add a portion at the beginning to achieve the desired pH,and then add the remainder concurrently with the difunctionalelectrophile.

Finally, it is desirable to conduct these polymerizations at highconcentrations. This reduces the amount of solvent which must be removedto isolate the product. Also, in certain cases the product precipitatesfrom the reaction solution near the end of the reaction, and may beisolated by simply decanting the solvent. Most of the inorganic saltwhich results from reaction of the acid acceptor is removed in thisprocess. The concentration is not critical, and may be from 0.5 to 50 wt%, expressed as weight of diamine to weight of solvent. A preferredrange is 5 to 20 wt %.

The product may be isolated by precipitation of the reaction solutioninto a solvent which is water miscible but is a poor solvent for theproduct. Examples of such solvents are acetone, methanol, ethanol,isopropanol.

Polycarbonates and Polyesters (of Formulae II and IV above)

The process previously described for the polyureas and polyamides wasused, with the following exceptions: Diphenols were used in place of thediamines: Suitable aromatic diphenols containing at least onesubstituent which is anionic at pH 7. These diphenols have identicalstructures to those of the diamines except that the amines are replacedwith hydroxyl groups. It is possible to pretreat the diols with one ortwo moles of base to form the mono- or diphenoxides. Some specificexamples are dipotassium 4,4'-dihydroxy(1,1'-biphenyl)-2,2'-disulfonate(HBPDS) and dipotassium 2,5-dihydroxy-1,4-benzenedisulfonate (HBDS).

The process conditions are much more critical due to the instability ofthe products in aqueous solutions. Of particular importance is pHcontrol. At pH levels below 7 the polymerization rate is very slow,while at high pH (>9) the carbonate or ester groups in the polymerundergo hydrolysis. A preferred pH range is 7 to 8, and it is desirableto have an automatic pH controller to maintain it. The useful range oftemperatures under which the polymerization can be conducted is morenarrow, 0° to 40° C. and preferably from 0° to 25° C.

After addition of the diacid chloride is complete, it is desirable towait for a time, typically 15 to 120 minutes to insure that theconversion of starting materials is complete. Additional base may beadded during this period, but the pH is never allowed to rise above thepreviously described limits. The product is isolated as a distributionof products as described above.

The invention will be further clarified by a consideration of thefollowing examples, which are intended to be purely exemplary of thepresent invention.

General Experimental

All solvents and reagents were obtained from commercial suppliers andused without further purification, except that BPDS was purified byrecrystallizing from dimethyl sulfoxide under nitrogen atmosphere.

PDS was prepared by the procedure described in DE 1,393,557 (whichdisclosure is hereby incorporated by reference), and the productrecrystalized from 1% (v/v) H₂ SO₄.

The inherent viscosity was measured at 0.5 g/dL in deionized water andHank's balanced salt solution (HBSS) (available from Sigma Chemical) at25° C. unless noted otherwise.

The water content of the purified diamines was determined by KarlFischer titration.

Proton and carbon nuclear magnetic resonance spectra were recorded on aVarian™ VXR 300 or an Varian™ Gemini 300 spectrometer. Samples weredissolved in D₂ O, unless otherwise noted. Where possible the numberaverage molecular weights of the oligomers was confirmed by integratingthe area of the resonances from the methyl groups of the end capsrelative to the aromatic resonances of the repeat unit. In many cases,particularly the polyamides prepared from BPDS or StDS and TPC, theresonances were too broad to be of value.

High pressure liquid chromatographic analysis (HPLC) were performed onan HP 1090 liquid chromatograph using a 200 mm×2.1 mm C-18 reverse phasecolumn. The column was eluted with a gradient solution startinginitially with of 35% of CH₃ CN and 65% of 5 mM tetra-n-butylammoniumsulfate and ending with 55% CH₃ CN and 45% of tetra-n-butylammoniumsulfate.

The phosgene reaction was carried out in a typical phosgenationapparatus having a stainless steel phosgene reservoir connected to aphosgene tank, nitrogen line and reaction feed line. The reservoir wasmounted on a scale and could be filled directly from the phosgene tankwhen needed. The differential weight of the reservoir before and afterthe reaction was reported as the amount of phosgene added. Unlessotherwise noted, a nitrogen carrier stream of 0.3 mL/min was maintainedthroughout the reaction. Phosgene was introduced at a rate of 0.9 mL/min(total gas flow of 1.2 mL/min during phosgene addition). In general athree-fold excess of phosgene was added to the reaction vessel. Astirring rate of 300 rpm was used and the solution maintained at 10° to15° C. throughout the course of the reaction.

The products were routinely dried in a vacuum oven at 40°-50° C. for aminimum of 15 hours.

STARTING MATERIALS Example A

Preparation of HBPDS, having the formula ##STR27##

To a 2 L flask equipped with an addition funnel and magnetic stir barwas added 49.99 g (0.145 mol) of4,4'-diamino(1,1'-biphenyl)-2,2'-disulfonic acid and 600 mL of water.The diamine was solubilized by the addition of 30 mL (0.15 mol) of 5MNaOH. To the resulting solution was added 20.56 g (0.298 mol) of sodiumnitrite. The reaction mixture was then cooled to 0° C. and 60 mL ofconcentrated H₂ SO₄ dissolved in 360 mL of water was added over 30 min.A yellow solid was formed. To the mixture was then added 300 mL of waterand the mixture maintained at 0° C. for one hour. The reaction mixturewas then filtered. The yellow solid was placed in a 1 L flask dissolvedin 800 mL of water, and heated until about 50 mL of water remained.Nitrogen gas was evolved during heating. To the concentrated solutionwas added 20.14 g (0.146 mol) of K₂ CO₃, followed by boiling thesolution. Absolute ethanol (1.5 L) was then added, and a brown solidprecipitated. The solid was filtered and dried overnight in a 50° C.oven. The product, HBPDS, was obtained in a yield of 32.33 g (53%), andfurther characterized by ¹ HMR δ6.70 (dd, 1H), 7.05 (d, 1H), 7.14 (d,1H).

Example B

Preparation of TPCS, having the formula ##STR28##

A 500 mL flask, equipped with a mechanical stirrer, thermometer andreflux condenser, was charged with 40.49 g (0.143 mol) of the monosodiumsalt of 2-sulfoterephthalic acid, 160 mL of chlorobenzene, 2.4 mL (0.031mol) of dimethylformamide, and 23 mL (0.315 mol) of thionyl chloride.The solution was heated to 105° C. and stirred for 2 hours undernitrogen. During this time evolution of gas was noted. The solution wascooled to room temperature and a solid precipitated. The solid wasfiltered and dried overnight in a vacuum oven at room temperature. Theproduct, as a pale yellow solid, was obtained in a yield of 20.56 g(47%).

To confirm the structure of the product, some of the product wasconverted to its methyl ester.

To a 25 mL flask, equipped with a magnetic stir bar and nitrogenbubbler, was added 0.9509 g (3.12 mmol) of the above product, 0.6874 g(6.47 mmol) of Na₂ CO₃, and 10 mL of methanol. After stirring thereaction mixture overnight at room temperature under nitrogen, the solidwas filtered, dried in a vacuum oven for 6 hours at room temperature,and determined that the dimethyl ester of the product had formed, beingcharacterized by ¹ H NMR δ3.34 (s, 6H), 7.39 (d, 1H), 7.97 (d, 1H), 8.26(s, 1H); ¹³ C NMR δ58.0, 136.0, 139.8, 140.9, 145.2, 146.8, 150.1,183.5, 186.4.

FINAL PRODUCTS Example 1

Preparation of BPDS/P/T, having the formula ##STR29##

Oligomer A (n=6)

To a 1L flask, equipped with a syringe port, thermometer well, pHelectrode, dry-ice condenser, phosgene gas inlet tube, and a mechanicalstirring device, was added 10.00 g (28.19 mmol) of BPDS, 1.35 g (9.40mmol) of toluidine hydrochloride, and 400 mL of water. The reactionmixture was stirred and cooled to 12° C. The stirred suspension was thenreacted with 13 mL of 5M NaOH until all the solids had dissolved. To thereaction mixture was then added 10.1 g (102 mmol) of phosgene over a 27min period. During the phosgene addition, 5M NaOH was added with asyringe as necessary to maintain the pH between 7 to 8 (occasionalextremes of pH 6 to 9 occurred). A total of 31 mL of NaOH was added.Stirring of the reaction mixture was continued for an additional 30 min,and then the pH was adjusted to 9.5 and the reaction mixture stirred foran additional. 30 min. The reaction mixture was transferred to a 2 Lflask and the crude product precipitated by the addition of 1000 mL ofacetone. The crude product was filtered and air-dried to yield 18.6 g ofan off-white powder having an M_(n) =2500. The inherent viscosity was0.39 dL/g in H₂ O, 0.15 dL/g in HBSS. The product was furthercharacterized by ¹ H NMR δ2.2 (br s), 6.7-7.4 (m), 7.9-8.3 (m).

Oligomer B (n=9)

When the procedure of Example 1A was repeated using the followingamounts of reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        BPDS            12.06  g     34.00                                            T.HCl           1.09   g     7.56                                             P               11.0   g     111.0                                            Water           400    mL                                                     ______________________________________                                    

the product, as a white powder, was obtained in a yield of 12 g andM_(n) =3600. The inherent viscosity was 0.52 dL/g in H₂ O, 0.2!dL/g inHBSS.

Example 2

Preparation of StDS/P/T, having the formula ##STR30##

Oligomer A (n=6)

When the procedure of Example 1A was repeated using the followingamounts of reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        StDS            10.58  g     28.00                                            T.HCl           1.34   g     9.33                                             P               7.4    g     74.8                                             Water           400    mL                                                     ______________________________________                                    

the product, as a yellow solid, was obtained in a yield of 7.4 g andM_(n) =2600. Inherent viscosity was 0.14 dL/g in H₂ O. The product wasfurther characterized by ¹ H NMR δ2.1 (br s), 6.7-8.1 (br m).

Oligomer B (n=9)

The procedure of Example 1A was repeated using the following amounts ofreagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        StDS            10.58  g     28.00                                            T.HCl           0.89   g     6.22                                             P               9.0    g     91.0                                             Water           400    mL                                                     ______________________________________                                    

About one-half of the suspension obtained after addition of acetone wasfiltered due to frit clogging problems. The product, as a yellow solid,was obtained in a yield of 3.5 g and M_(n) =3800. Inherent viscosity was0.18 dL/g in H₂ O.

Example 3

Preparation of PDS/P/T, having the formula ##STR31##

Oligomer A (n=9)

When the procedure of Example 1A was repeated using the followingquantities of reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        PDS             3.50   g     13.05                                            T.HCl           0.416  g     2.90                                             P               4.3    g     43.5                                             Water           225    mL                                                     ______________________________________                                    

the product, as a brown powder, was obtained in a yield of 2.95 g andM_(n) =2900. Inherent viscosity was 0.12 dL/g in H₂ O and 0.07 dL/g inHBSS.

Oligomer B (n=15)

When the procedure of Example 1A was repeated using the followingamounts of reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        PDS             3.50   g     13.05                                            T.HCl           0.250  g     1.74                                             P               4.2    g     42.0                                             Water           225    mL                                                     ______________________________________                                    

the product, as a brown powder, was obtained in a yield of 3.83 g andM_(n) =4650. Inherent viscosity was 0.12 dL/g in H₂ O and 0.14 dL/g inHBSS.

Example 4

Preparation of HBDS/P/C, having the formula ##STR32##

Oligomer A (n=6)

To a 1L flask, equipped with a syringe port, a thermometer well,mechanical stirrer, pH electrode, dry ice condenser, and a phosgeneinlet tube, was added 10.16 g (29.35 mmol) of HBDS, 1.06 g (9.81 mmol)of p-cresol, and 400 mL of water. The reaction mixture was cooled to 10°C. with nitrogen flowing into the flask through the phosgene inlet. Thestirred reaction mixture was treated with 5M sodium hydroxide until thepH of the solution was 8.0. To the reaction mixture was added 10.5 g(106.0 mmol) of phosgene over 35 min along with 42 mL of 5M sodiumhydroxide as needed to maintain the pH of the solution between 7.0 to7.5. After the phosgene addition was complete, the solution was allowedto stir for 20 min at 10° C. The dry ice was then removed from thecondenser and the solution stirred an additional 30 min at 10° C. inorder to allow the excess phosgene to evaporate. The aqueous solutionwas transferred to a 2 L flask and 100 mL of water used to rinse thereaction vessel was added. The product was precipitated by the additionof 1000 mL of acetone, filtered, and dried overnight in a vacuum oven atroom temperature. The yield of product was 2.11 g, the inherentviscosity of the solid was 0.30 dL/g in H₂ O, and M_(n) =2300.

Example 5

Preparation of HBPDS/P/C, having the formula ##STR33##

Oligomer A (n=6)

When the procedure of Example 4 was repeated using the following amountsof reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        HBPDS           12.35  g     29.25                                            p-cresol        1.07   g     9.91                                             P               10.1   g     102                                              Water           400    mL                                                     ______________________________________                                    

the pH of the initial solution was 10.0 and was adjusted to pH 8.1 withconcentrated hydrochloric acid. The phosgene was added over 32 min with31 mL of 5M sodium hydroxide to maintain the pH between 7.5 and 8.0.After the phosgene was allowed to evaporate, the reaction mixture wastransferred to a 2 L flask and 100 mL of water used to rinse thereaction vessel was added. The product was precipitated by the additionof 1400 mL of acetone, filtered, and dried overnight in a vacuum oven atroom temperature. The yield of product was 1.89 g, the inherentviscosity of the solid was 0.17 dL/g in H₂ O, and M_(n) =2700. Theproduct was further characterized by ¹ H NMR δ2.2 (s), 7.0 (s), 7.2 (s),7.5 (br s).

Example 6

Preparation of HBPDS/TPC, having the formula ##STR34##

Oligomer A (n=4)

A 500 mL flask, equipped with a reflux condenser, addition funnel, andmechanical stirrer, was charged with 7.92 g (18.7 mmol) of HBPDS, 3.16 g(37.6 mmol) of sodium bicarbonate, 125 mL of water, and 25 mL ofmethylene chloride. To the stirred reaction mixture was added 3.80 g(18.7 mmol) of TPC in 100 mL of methylene chloride over one hour. Theresulting solution was stirred for 1.5 hours at room temperature undernitrogen. The solution was then transferred to a 2 L flask and 100 mL ofwater used to rinse the reaction vessel was added. Acetone was added in250 mL increments to break the emulsion. After 1000 mL acetone wasadded, a solid was formed on the bottom of the flask which looked likebeads filled with water. The solution was filtered, redissolved in 250mL of water, precipitated with 750 mL of acetone, filtered, and driedovernight in a vacuum oven at room temperature. The brown solid weighed4.89 g, the inherent viscosity of the solid was 0.16 dL/g in H₂ O, andM_(n) =2100. The product was further characterized by ¹ H NMR δ2.2 (s),7.0 (br s), 7.25 (br s), 7.5 (br s), 8.0 (br s).

Example 7

Preparation of HBDS/TPC, having the formula ##STR35##

Oligomer A (n=3)

The procedure of Example 6 was repeated using the following amounts ofreagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        HBDS            6.51   g     18.8                                             NaHCO.sub.3     3.15   g     37.5                                             CH.sub.2 Cl.sub.2                                                                             125    mL                                                     TPC             3.84   g     18.9                                             Water           125    mL                                                     ______________________________________                                    

The resulting solution was stirred for 1.5 hours at room temperatureunder nitrogen. The solution was then transferred to a 1L flask and 100mL of water used to rinse the reaction vessel was added. To the flaskwas added 450 mL of acetone to break the emulsion. There was aprecipitate formed in the lower water layer. The solution wastransferred to a separatory funnel and the lower layer separated. Thewater solution was then treated with 500 mL of acetone. A beige solidwas formed, filtered, and dried over two days in a vacuum oven at roomtemperature. The product weighed 4.38 g, the inherent viscosity of thesolid was 0.05 dL/g. Analysis by ¹ H NMR and HPLC revealed significantamounts of starting diphenol.

In order to remove the unreacted starting material, 2.0 g of the aboveisolated solid was dissolved in 200 mL water. The product wasprecipitated by the addition of 700 mL of acetone, filtered, and driedovernight in a vacuum oven at room temperature. The solid productweighed 0.41 g, the inherent viscosity of the solid was 0.11 dL/g in H₂O, and M_(n) =1300.

Example 8

Preparation of BPDS/TPC/MBC, having the formula ##STR36##

Iligomer A (n=6)

To a Waring blender was added 200 mL of deionized water and 2.65 g (25.0mmol) of sodium carbonate and the mixture stirred at low speed untildissolved. To the reaction mixture was added 2.217 g (6.25 mmol) of BPDSvia a powder addition funnel. The funnel was rinsed with 50 mL of waterinto the mixture. A clear colorless sodium salt solution was formed.

A second solution having 1.088 g (5.357 mmol) of TPC and 0.193 mL (236mg, 1.786 mmol) of MBC in 200 mL of chloroform was prepared. Thesolution was immediately added in one portion to the sodium saltsolution with vigorous stirring. The resultant white slurry was stirredat low speed for 15 min.

After sitting for 15 min, the slurry was transferred to a 2 L flask andthe blender washed with about 200 mL of water which was added to theslurry. To the slurry was added 200 mL of acetone. The emulsion brokeinto a two-phase system with no visible precipitate. The lower layer wasremoved via separatory funnel; the upper layer was returned to theflask. To the flask was added 450 mL of acetone which effectedprecipitation. The precipitate was filtered through three layers ofcheesecloth. The residual solvents were removed from the whitegelatinous product by firmly squeezing the cheesecloth. The crudeproduct was dissolved in 600 mL of water and reprecipitated by dilutionto a total volume of 1600 mL with acetone. The precipitate was againcollected, dissolved in 150 mL of water, and precipitated by adding 850mL of acetone. The precipitate was collected as before, dried in avacuum oven overnight at 35° to 36° C. to yield 0.8 g of a fibrous whiteproduct.

A second crop of product was obtained from the original mother liquorhaving a yield of 0.9 g. The combined solids were dissolved in 130 mL ofwater and precipitated by adding 500 mL of acetone to give 1.26 g, of aoff-white solid, M_(n) =3450. Inherent viscosity was 3.85 dL/g in H₂ O.The product was further characterized by ¹ H NMR δ2.1 (s), 7.44 (s),7.78 (s), 8.02 (br s).

Oligomer B (n=3)

When the procedure of Example 8A was repeated using the followingquantities of reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        BPDS            2.217  g     6.25                                             TPC             0.952  g     4.688                                            MBC             412    mg    3.125                                            Na.sub.2 CO.sub.3                                                                             2.65   g                                                      ______________________________________                                    

the product, as an off-white powder, was obtained in a yield of 1.58 gand M_(n) =2000. Inherent viscosity was 1.83 dL/g in H₂ O and 2.4!dL/gin HBSS.

Oligomer C (n=9)

When the procedure of Example 8A was repeated using the followingquantities of reagents:

    ______________________________________                                        REAGENT         AMOUNT   mmol                                                 ______________________________________                                        BPDS            2.217  g     6.250                                            TPC             1.142  g     5.625                                            MBC             165    mg    1.250                                            Na.sub.2 CO.sub.3                                                                             2.65   g                                                      ______________________________________                                    

the white, fibrous product, was obtained in a yield of 1.42 g and M_(n)=4900. Inherent viscosity was 4.23 dL/g in H₂ O.

BIOLOGICAL DATA Example I ABILITY OF AN ANTI-HIV OLIGOMER TO PREVENTSYNCYTIA FORMATION AND EXPRESSION OF P24 VIRAL CORE ANTIGEN USING JMCELLS AND GB8 VIRUS STRAIN

To show that an oligomer of the invention blocks HIV infection, CD4⁺T-cells (JM) were exposed to a clinical isolate of HIV-I, GB8. The viruswas first incubated with an oligomer for 15 minutes and then the cellswere added. After 2 hours adsorption, the virus innoculum was removedand the cells were washed three times to remove traces of input virus.Antiviral activity was determined after 3 days incubation by plottingthe mean number of syncytia found in quadruple cultures against log₁₀concentration of anionic polymer or of other test compounds. The potencyof an oligomer was also measured by assaying vital core antigen (P24test-Abbott) in the supernatant fluid. Heparin, dextran sulfate, rs CD4,ATZ and/or ddC data, when included in any of the following Tables, areprovided as positive controls.

                  TABLE I                                                         ______________________________________                                                  CONC.              P24    %                                         COMPOUND  μg/ml                                                                              SYNCYTIA   (pg/mL)                                                                              CONTROL                                   ______________________________________                                        Control   --      +++        >453600                                                                              100                                       Heparin   5.0     0          2500   <0.1                                                2.5     +/0        25775  <0.1                                                1.25    +/0        N.A.   N.A.                                                0.6     ++         44570  0.1                                       Example 1A                                                                              5.0     0          N.D.   N.A.                                                2.5     0          96     <0.1                                                1.25    0          541    <0.1                                                0.6     +          37355  0.13                                      Example 1B                                                                              5.0     0          465    <0.1                                                2.5     0          365    <0.1                                                1.25    +          35890  <0.1                                                0.6     +          32820  0.1                                       ______________________________________                                         N.D. = not detected                                                           N.A. = not assayed                                                       

Example II

Virus infection of JM cells was carried out in the presence of differentconcentrations of test compounds. JM cells (1×10⁵) and 50-100 syncytialforming units of virus (GB8) were added to duplicate wells of a tissueculture plate containing 1 mL volumes of growth medium with or withoutdrug. The plate Was incubated for 2 days at 37° C. and then scored forthe presence of syncytia. At the same time the cells were washed and thegrowth medium replaced. After a further two days incubation, the cellfree supernatant fluids were harvested and assayed for levels of P24viral core antigen using the Coulter™ HIV Antigen assay. The results aregiven in Tables II-IV. In the Tables, N.D.=not detected and N.A.=notassayed.

                  TABLE II                                                        ______________________________________                                        COM-   CONC.   SYNCYTIA              P24                                      POUND  μg/mL                                                                              (2 DAYS)   MEAN  %    (units/mL)                                                                           %                                 ______________________________________                                        Control                                                                              --      39, 27, 42, 31                                                                           42    100  3.6 × 10.sup.5                                                                 100                                              42, 41, 51, 13                                                                57, 53, 56, 38                                                                41, 47, 41, 45                                                                52                                                             rs CD4 5        0         0     0    4.4 × 10.sup.4                                                                 12                                Heparin                                                                              10       0, 0      0     0    1.1 × 10.sup.4                                                                 3                                        3        0, 0      0     0    1.7 × 10.sup.4                                                                 5                                        1        2, 1      2     5    2.8 × 10.sup.4                                                                 8                                        0.3     21, 22     22    52   4.1 × 10.sup.4                                                                 11                                       0.1     28, 20     24    57   N.A.   N.A.                                     0.03    39, 19     29    69   N.A.   N.A.                                     0.01    33, 42     38    90   N.A.   N.A.                              Example                                                                              10       0, 0      0     0    N.D.   N.D.                              1A     3        0, 0      0     0    N.D.   N.D.                                     1        0, 0      0     0    9.1 × 10.sup.3                                                                 3                                        0.3      9, 19     14    33   4.0 × 10.sup.4                                                                 11                                       0.1     21, 28     25    58   4.0 × 10.sup.5                                                                 100                                      0.03    52, 52     52    123  4.3 × 10.sup.5                                                                 100                                      0.01    54, 66     60    143  N.A.   N.A.                              Example                                                                              10       0, 0      0     0    N.D.   N.D.                              1B     3        0, 0      0     0    N.D.   N.D.                                     1        0, 0      0     0    1.6 × 10.sup.3                                                                 0.4                                      0.3      2, 0      1     2    3.8 × 10.sup.4                                                                 11                                       0.1     36, 13     25    58   4.4 × 10.sup.5                                                                 100                                      0.03    43, 40     42    100  4.15   100                                      0.01    40, 54     47    112  N.A.   N.A.                              Example                                                                              20       9, 1      5     12   N.D.   N.D.                              3A     10       4, 2      3     7    4.1 × 10.sup.4                                                                 11                                       5       15, 14     15    36   3.6 × 10.sup.5                                                                 100                                      2.5     37, 38     38    90   2.5 × 10.sup.5                                                                 69                                       1.25    27, 13     20    48   4.3 × 10.sup.5                                                                 100                                      0.6     46, 55     51    120  N.A.   N.A.                              Example                                                                              100      0, 0      0     0    N.D.   N.D.                                     30       0, 0      0     0    N.D.   N.D.                                     10       0, 0      0     0    N.D.   N.D.                                     3        0, 0      0     0    4.4 × 10.sup.4                                                                 12                                       1        2, 3      3     7    4.34   12                                ______________________________________                                    

                  TABLE III                                                       ______________________________________                                                 CONC.                        P24                                     COMPOUND μg/mL                                                                              SYNCYTIA  MEAN  %    (pg/mL)                                                                             %                                 ______________________________________                                        Control  --      46, 52, 69                                                                              69    100  332300                                                                              100                                                79, 84, 69                                                                    81, 67, 68                                                                    71, 64, 75                                                   rsCD4    10       0, 0      0         5340  1.6                                        1       15, 24    20    28   88700 27                                         0.1     35, 44    40    57   202000                                                                              61                                Heparin  100      0, 0      0         989   0.3                                        10       0, 0      0         70700 21                                         1        9, 17    13    19   211000                                                                              63                                Example 8A                                                                             500      0, 0      0         N.A.  N.A.                                       50       0, 0      0         11600 3.5                                        5       39, 31    35    51   268599                                                                              81                                ______________________________________                                    

Example III ABILITY OF VARIOUS ANTI-HIV OLIGOMERS TO PREVENTVIRUS-INDUCED CELL DEATH USING MT4 CELLS AND STRAIN RF

Various oligomers were dissolved in RPMI and were then assayed foranti-HIV activity by making doubling dilutions of the solutions across a96 well microtitre plate. To each well were then added 5×10⁴ cells and100 TCID50 of virus and the plates incubated at 37° C. for 7 days. MTTwas added to each well and the plates incubated for a further 2 hours.The blue formazan crystals were dissolved using acidic isopropanol, andthe absorbance measured at 540 nm. The results are given in Table IV.

                  TABLE IV                                                        ______________________________________                                                                 ED.sub.50                                                                             TD.sub.50                                    COMPOUND   MW.sup.a      μg/mL                                                                              μg/mL                                     ______________________________________                                        Heparin    10,000-40,000 4.6     >100                                         Example 1B 4,168         2.2     >100                                         Example 1A 2,958         1.6     >100                                         Example 8C 5,290         2.2     >100                                         Example 8A 3,689         1.5     >100                                         Example 8B 2,180         2.1     >100                                         Example 2B 4,204         2.5     >100                                         Example 2A 2,883         1.9     >100                                         Example 3B 5,314         1.7     >100                                         Example 3A 3,284         >>10    >100                                         ______________________________________                                         .sup.a Number average molecular weight                                   

Example IV ABILITY TO PRETREAT CELLS WITH VARIOUS OLIGOMERS AND BLOCKHIV-I INFECTION USING JM CELLS AND GB8 STRAIN OF HIV-I

JM cells were pretreated overnight at 37° C. with different compounds at20 μg/mL or left untreated. The cells were washed 3 times in RPMI mediumand then infected with HIV-I (GB8) for 2 hours at room temperature. Thecells were again washed 3 times in RPMI medium and resuspended in freshmedium prior to being distributed into duplicate wells and incubated at37° C. After 2 days syncytia were scored and the cell free supernatantfluid harvested and assayed for P24 viral core antigen using theCoulter™ HIV antigen assay. The results are given in Table V.

                  TABLE V                                                         ______________________________________                                                    MEAN               P24                                            COMPOUND    SYNCYTIA  %        (pg/mL)                                                                             %                                        ______________________________________                                        Control     119       100      28290 100                                      Example 1A   14        12       2623  9                                       Example 1B   52        44       2790  10                                      Example 3A  153       129      26880  95                                      Heparin     136       114      29090 103                                      Dextran Sulfate                                                                           184       155      28710 101                                      ______________________________________                                    

Example V ABILITY OF AN ANTI-HIV-I OLIGOMER TO PREVENT SYNCYTIAFORMATION AND P24 VIRAL CORE ANTIGEN EXPRESSION BY DIFFERENT VIRALSTRAINS (GB8 AND RF) AND CELLS (JM AND C8166)

Cells were infected with strain RF or GB8 for 24 hours at 37° C. at amultiplicity of infection of 0.001. Cells were washed three times toremove residual virus and then replated into fresh growth medium. Cellswere then treated for 24 and 48 hours post-infection (p.i.) with theindicated concentrations of test compounds. Syncytia and P24 antigenlevels were determined on the indicated days p.i. by methods describedbefore. Results are presented in Tables VI-VIII.

                                      TABLE VI                                    __________________________________________________________________________    EFFECT OF TREATING HIV-I (GB8) - INFECTED CELLS (JM)                          24 HOURS POST-INFECTION                                                                   TIME OF                                                                       ADDITION     P24                                                              POST- SYNCYTIA/                                                                            pg/mL                                                       DOSAGE                                                                             INFECTION                                                                           WELL   DAY 6                                                                              %                                               COMPOUND                                                                             (μM)                                                                            (HOURS)                                                                             DAY 3 p.i..sup.a                                                                     p.i..sup.a                                                                         CONTROL                                         __________________________________________________________________________    Control                                                                              0    --    >100   1.03 × 10.sup.6                                                              100.                                            Example 1A                                                                           2.5   0      0    4.22 0.04                                            Example 1A                                                                           2.5  24      0    1.21 × 10.sup.4                                                              1.2                                             Example 1A                                                                           1.2  24    <10    1.5 × 10.sup.4                                                               1.5                                             Example 1A                                                                           0.62 24    <20    5.6 × 10.sup.4                                                               5.4                                             Example 1A                                                                           0.31 24    >50    1.65 × 10.sup.5                                                              16.0                                            __________________________________________________________________________     .sup.a p.i. means post infection                                         

The results in Table VI above indicate that events associated with vitalinduced cytopathological changes such as syncytia formation can beinhibited even when compounds are administered to previously infectedcells. These results also indicate that the anionic oligomers areworking by a mechanism in addition to blocking viral attachment to theCD4 cell surface protein.

                                      TABLE VII                                   __________________________________________________________________________    EFFECT OF TREATING HIV-II (RF) - INFECTED CELLS (C8166)                       24 HOURS POST-INFECTION                                                                   TIME OF                                                                       ADDITION       P24                                                            POST-          pg/mL                                                     DOSAGE                                                                             INFECTION                                                                           SYNCYTIA/WELL                                                                          DAY 6                                                                              %                                             COMPOUND                                                                             (μM)                                                                            (HOURS)                                                                             DAY 2                                                                             DAY 3                                                                              p.i..sup.a                                                                         CONTROL                                       __________________________________________________________________________    Control                                                                              0    --    +   +++  9.5 × 10.sup.5                                                               100.                                          ddC    10    0    0   0    1.3 × 10.sup.4                                                               1.4                                           ddC    10   24    +   +++  4.2 × 10.sup.5                                                               44.2                                          AZT    10    0    0   0    1.0 × 10.sup.4                                                               1.1                                           AZT    10   24    +   ++   4.4 × 10.sup.4                                                               4.6                                           Example 1A                                                                           10    0    0   0    1.6 × 10.sup.4                                                               1.7                                           Example 1A                                                                           10   24    0   0    9.2 × 10.sup.3                                                               1.0                                           Example 1A                                                                           5    24    0   0    9.3 × 10.sup.3                                                               1.0                                           Example 1A                                                                           2.5  24    0   0    9.78 × 10.sup.4                                                              10.2                                          Example 1A                                                                           1.25 24    0   ++   1.5 × 10.sup.6                                                               100.                                          Example 1A                                                                           0.62 24    +   +++  7.0 × 10.sup.5                                                               74.                                           __________________________________________________________________________     .sup.a p.i. means post infection                                         

The results in Table VII above indicate that the oligomers of thisinvention are effective against different viral strains and differentcell types even when added 24 hours after virus infection.

                                      TABLE VIII                                  __________________________________________________________________________    EFFECT OF TREATING HIV-I (GB8) - INFECTED CELLS (JM)                          48 HOURS POST-INFECTION                                                                   TIME OF                                                                       ADDITION                                                                            SYNCYTIA/                                                               POST- WELL.sup.b     %                                                   DOSAGE                                                                             INFECTION                                                                           DAY 3 DAY 6                                                                             P24  CON-                                         COMPOUND                                                                             (μM)                                                                            (HOURS)                                                                             p.i..sup.a                                                                          p.i..sup.a                                                                        pg/mL                                                                              TROL                                         __________________________________________________________________________    Control                                                                              0    --    69    Cells                                                                             1.1 × 10.sup.5                                                               100.                                                           61    Degen-                                                                  70    erated                                                Example 1A                                                                           1.2   0     0    0   4.5 × 10.sup.2                                                               0.41                                                            0    0                                                                        0    0                                                     Example 1A.sup.b                                                                     1.2  48    19    2   2.1 × 10.sup.4                                                               19.0                                                           10    5                                                                       12    9                                                     __________________________________________________________________________     .sup.a p.i. means post infection                                              .sup.b Approximately 50 syncytia/well were observed at 48 hours p.i. in       the virus control wells. At this time, wells received 5 μg/mL of the       oligomer of Example 1A and were incubated further. Syncytia were scored o     day 3 p.i. At 4 days p.i. cells were washed in media containing 5 μg/m     of the oligomer of Example 1A and incubated further in 5 μg/mL of the      oligomer of Example 1A. Virus control cells were washed in media as above     without test compound and reincubated in parallel. On day 6 p.i. the          cellfree media of all samples were collected and viral P24 antigen levels     were determined.                                                         

The results of these studies show that the oligomers of Example 1Acleared cultures of syncytia, stabilized the infection and reduced virusantigen levels in cells having preestablished infections.

Example VI

Protocol: C8166 cells were infected with HIV (Strain RF) for 1 hour atroom temperature to give a multiplicity of infection of approximately0.01 infectious units per cell. The cells were washed three times andresuspended in fresh medium prior to being distributed into duplicatewells containing different concentrations of test compound. After 2 daysat 37° the cells were observed for the presence of syncytia and thesupernatant fluid assayed for p24 vital core antigen using the CoulterHIV antigen assay.

                  TABLE IX                                                        ______________________________________                                        Anti-HIV Activity of Various Phenyl and Biphenyl                              Disulfonic Acid Polyester and Polycarbonate Oligomers                                  OLIGOMER                    %                                                 CONC.     SYNCYTIA  p24 (pg/ml)                                                                           OF VIRUS                                 COMPOUND μg/ml  Day 2     Day 2   CONTROL                                  ______________________________________                                        Virus    --        +++        3.2 × 10.sup.3                                                                 100                                      Control                                                                       Example 6                                                                              100       0         neg      0                                                50        0         neg      0                                                25        0/+       neg      0                                                12        0/+       neg      0                                       Example 4                                                                              100       ++/+++    1.93 × 10.sup.3                                                                 60                                                50        ++/+++    2.82 × 10.sup.3                                                                 88                                                25        ++/+++    4.82 × 10.sup.3                                                                 100                                               12        ++/+++    3.05 × 10.sup.3                                                                 95                                       Example 7                                                                              100       0/+       neg      0                                                50        ++         8.7 × 10.sup.2                                                                 27                                                25        ++/+++    1.45 × 10.sup.3                                                                 45                                                12        ++/+++    3.14 × 10.sup.3                                                                 98                                       Example 5                                                                              100       +++       1.06 × 10.sup.3                                                                 33                                                50        +++       2.78 × 10.sup.3                                                                 87                                                25        +++       2.32 × 10.sup.3                                                                 73                                                12        +++       3.25 × 10.sup.3                                                                 100                                      AZT      1         0         neg      0                                                0.1       0         neg      0                                                0.1       0/+       neg      0                                       ______________________________________                                    

Example VII

JM cells were infected with HIV (Strain GB8) to give approximately 200syncytia/1×10⁵ cells after 3 days; virus infection was for 1 hour atroom temperature. The cells were washed and resuspended in fresh mediumbefore being distributed into duplicate wells of a tissue culture platecontaining different concentrations of test compound. After 3 days thecells were observed, syncytia counted and the supernatant fluid assayedfor p24 viral core antigen using the Coulter HIV Ag assay.

                  TABLE X                                                         ______________________________________                                                 OLIGOMER                                                                      Conc.       MEAN SYNCYTIA                                                                              p24 pg/ml*                                  COMPOUND μg/ml    3 days p.i.  3 days p.i.                                 ______________________________________                                        Virus    --          >00          5.2 × 10.sup.3                        ddC      10          0            neg                                                  1           0            neg                                                  0.1         2            neg                                                  0.01        80           5.4 × 10.sup.3                        Example 6                                                                              200         0            --                                                   100         0            neg                                                  50          12           neg                                                  25          25           6.8 × 10.sup.3                        Example 7                                                                              200         0            neg                                                  100         7            neg                                                  50          24           neg                                                  25          43           neg                                         Example 5                                                                              200         14           neg                                                  100         22           neg                                                  50          68           neg                                                  25          >200         6.7 × 10.sup.1                        Example 4                                                                              200         Toxic        --                                                   100         Toxic        --                                                   50          64           neg                                                  25          95           6.5 × 10.sup.3                        ______________________________________                                         *supernatant fluids screened at 1/100 dilution.                          

Other embodiments of the invention will be apparent to those skilled inthe art from a consideration of this specification or practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with the true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A pharmaceutical formulation comprising apharmaceutically acceptable carrier and a rigid backbone, water solubleoligomer, having a molecular weight less than 10,000, recurring unitscoupled by carbonyl linking moieties, anionic groups and predominantlylinear geometry in an aqueous medium and which is represented by any oneof the following formulae:A) a polyurea of the, formula: ##STR37##wherein: R represents hydrogen, C₁ -C₄ alkyl, phenyl, or phenylsubstituted with from 1 to 2 R¹ moieties and up to 3 substituentsindependently selected from a chloro, bromo or C₁ -C₄ alkyl; R¹represents --SO₃ R², --CO₂ R², --PO₃ (R²)₂, or --OPO₃ R² ; R² representshydrogen or a pharmaceutically-acceptable cation; m is 0 or 1, with theproviso that when m is 0, R is a hydrogen atom; X represents ##STR38## Yrepresents --CO₂ --, --C.tbd.C--, --N═N--, ##STR39## n is an integerfrom 3 to 50; and R³ represents --R or --X--NH₂, where R and X aredefined as before; B) a polycarbonate of the formula: ##STR40## wherein:X and n are defined as in Formula I, above; X¹ represents a HO--X--,where X is defined as in Formula I above, C₁ -C₄ alkyl, phenyl, orphenyl substituted with from 1 to 2 R¹ moieties and up to 3 substituentsindependently selected from a chloro, bromo or C₁ -C₄ alkyl; and X²represents a hydrogen atom, or --CO₂ X¹, where X¹ is defined as above;C) a polyester of the formula ##STR41## wherein: X and n are defined asin Formula I, above; R⁴ represents --R², as defined in Formula I, above,or --X¹, as defined in Formula II, above; R⁵ represents ##STR42## whereR⁴ is defined as in Formula III, above or --R² where R² is defined as inFormula I, above; X³ represents ##STR43## wherein R¹ and Y are definedas in Formula I, above; or D) a polyamide of the formula: ##STR44##wherein: X and n are defined as in Formula I, above; X³ is defined as inFormula III, above; R⁶ represents H₂ N--X--NH--, R² O--, RNH-- orR--C(O)--NH--X--NH--, where R, R² and X are defined as in Formula I,above; R⁷ represents hydrogen, ##STR45## where R and R² are defined asin Formula I, above; and X³ is defined as in Formula III, above.
 2. Thepharmaceutical formulation of claim 1 wherein the oligomer is in theform of its pharmaceutically-acceptable salt.
 3. The pharmaceuticalformulation of claim 1 wherein the number average molecular weight ofthe oligomer is from about 500 to about 10,000.
 4. The pharmaceuticalformulation of claim 1 wherein the number average molecular weight ofthe oligomer is from about 1,000 to about 6,000.
 5. The pharmaceuticalformulation of claim 1 wherein the oligomer is a polyurea of Formula 1wherein R and R³ are 4-methylphenyl, m is 1, n is 3 to 15, X is##STR46## and R² is hydrogen or a pharmaceutically-acceptable cation. 6.The pharmaceutical formulation of claim 5 wherein the oligomer is of theformula: ##STR47## wherein R² is defined as above in claim 5 and n is3-9.
 7. The pharmaceutical formulation of claim 6 wherein the oligomeris of the formula: ##STR48## wherein R² is defined as above in claim 5.8. The pharmaceutical formulation of claim 5 wherein the oligomer is ofthe formula: ##STR49## wherein R² is defined as above in claim 5 and nis 3-9.
 9. The pharmaceutical formulation of claim 5 wherein theoligomer is of the formula: ##STR50## wherein R² is defined as above inclaim 5 and n is 3-9.
 10. The pharmaceutical formulation of claim 1wherein the oligomer is a polycarbonate of Formula II wherein X¹ is a4-methylphenyl; X² is --CO₂ --(4-methylphenyl), n is 3 to 15 and X is##STR51## and R² is hydrogen or a pharmaceutically-acceptable cation.11. The pharmaceutical formulation of claim 10 wherein the oligomer isof the formula: ##STR52## wherein R² is defined as above in claim 10 andn is 3-.
 12. The pharmaceutical formulation of claim 10 wherein theoligomer is of the formula: ##STR53## wherein R² and n are defined asabove in claim
 10. 13. The pharmaceutical formulation of claim 1 whereinthe oligomer is a polyester of Formula III wherein R⁴ and R⁵ arehydrogen, n is 3 to 15, X³ represents ##STR54## and X represents:##STR55## and R² is hydrogen or a pharmaceutically-acceptable cation.14. The pharmaceutical formulation of claim 13 wherein the oligomer isof the formula: ##STR56## wherein n is 3-9 and R² is defined as in claim13.
 15. The pharmaceutical formulation of claim 13 wherein the oligomeris of the formula: ##STR57## wherein n is 3-9 and R² is defined as inclaim
 13. 16. The pharmaceutical formulation of claim 1 wherein theoligomer is a polyamide of Formula IV wherein R⁶ isR--C(O)--NH--X--NH--; R⁷ is R--C(O)-- wherein R is 4-methylphenyl; n is3 to 15; X³ represents ##STR58## and X represents: ##STR59## and R² ishydrogen or a pharmaceutically-acceptable cation.
 17. A pharmaceuticalformulation comprising a pharmaceutically acceptable carrier and amixture of specific oligomers of the formula:A) a polyurea of theformula: ##STR60## wherein: R represents hydrogen, C₁ -C₄ alkyl, phenyl,or phenyl substituted with from 1 to 2 R¹ moieties and up to 3substituents independently selected from a chloro, bromo or C₁ -C₄alkyl; R¹ represents --SO₃ R², --CO₂ R², --PO₃ (R²)₂, or --OPO₃ R² ; R²represents hydrogen or a pharmaceutically-acceptable cation; m is aninteger 0 or 1, with the proviso that when m is 0, R is hydrogen; Xrepresents ##STR61## Y represents --CO₂ --, --C.tbd.C--, --N═N--,##STR62## n is an integer from 3 to 50; and R³ represents --R or--X--NH₂, where R and X are defined as before; B) a polycarbgnate of theformula: ##STR63## wherein: X and n are defined as in Formula I, above;X¹ represents HO--X--, where X is defined as in Formula I, above, C₁ -C₄alkyl, phenyl, or phenyl substituted with from 1 to 2 R¹ moieties and upto 3 substituents independently selected from a chloro, bromo or C₁ -C₄alkyl; and X² represents hydrogen, or --CO₂ X¹, where X¹ is defined asabove; C) a polyester of the formula ##STR64## wherein: X and n aredefined as in Formula I, above; R⁴ represents --R² or --X¹ as definedabove; R⁵ represents ##STR65## where R⁴ is defined as above or --R², asdefined above; X³ represents ##STR66## wherein R¹ and Y are defined asin Formula I, above or D) a polyamide of the formula: ##STR67## wherein:X and n are defined as in Formula I, above; X³ is defined as in FormulaIII, above; R⁶ represents H₂ N--X--NH--, R² O--, RNH-- orR--C(O)--NH--X--NH--, where R, R² and X are defined as in Formula I,above; R⁷ represents hydrogen, ##STR68## where R and R² are defined asin Formula I, above; and X³ is defined as in Formula III, above.
 18. Apharmaceutical formulation comprising a detergent and an oligomerrepresented by any one of the following formuale:A) a polyurea of theformula: ##STR69## wherein: R represents hydrogen, C₁ -C₄ alkyl, phenyl,or a phenyl substituted with from 1 to 2 R¹ moieties and up to 3substituents independently selected from a chloro, bromo or C₁ -C₄alkyl; R¹ represents --SO₃ R², --CO₂ R², --PO₃ (R²)₂, or --OPO₃ R² ; R²represents a hydrogen atom or a pharmaceutically-acceptable cation; m isan integer 0 or 1, with the proviso that when m is 0, R is a hydrogenatom; X represents ##STR70## Y represents --CO₂ --, --C.tbd.C--,--N═N--, ##STR71## n is an integer from 3 to 50; and R³ represents --Ror --X--NH₂, where R and X are defined as before; B) a polycarbonate ofthe formula: ##STR72## wherein: X and n are defined as in Formula I,above; X¹ represents HO--X--, where X is defined as in Formula I, above,C₁ -C₄ alkyl, phenyl, or phenyl substituted with from 1 to 2 R¹ moietiesand up to 3 substituents independently selected from chloro, bromo or C₁-C₄ alkyl; and X² represents hydrogen, or --CO₂ X¹, where X¹ is definedas above; C) a polyester of the formula ##STR73## wherein: X and n aredefined as in Formula I, above; R⁴ represents --R² as defined in FormulaI, above, or --X¹, as defined in Formula II, above; R⁵ represents##STR74## where R⁴ is defined as in Formula III, above or --R² where R²is defined as in Formula I, above; X³ represents ##STR75## wherein R¹and Y are defined as in Formula I, above; or D) a polyamide of theformula: ##STR76## wherein: X and n are defined as in Formula I, above;X³ is defined as in Formula III, above; R⁶ represents H₂ N--X--NH--, R²O--, RNH-- or R--C(O)--NH--X--NH--, where R, R² and X are defined as inFormula I, above; R⁷ represents a hydrogen atom, ##STR77## where R andR² are defined as in Formula I, above; and X³ is defined as in FormulaIII, above.
 19. The pharmaceutical formulation of claim 1 in the form ofa liquid, powder, douche, jelly or lotion.
 20. The pharmaceuticalformulation of claim 16 wherein the oligomer is of the formula:##STR78## wherein R² is defined as in claim 16 and n is 3-9.